The number of deaths from cancers is ever increasing in the U.S. year by year and-will presumably exceed 600,000 in 1996. About 24% of these deaths are-attributable to brain tumors and the metastases of various primary tumors to the brain. Since the metastasis entails hyper intracranial pressure and dysfunction of the brain, metastatic brain tumors are a major cause of the deaths from cancers (Rev. Neurol. (Paris) 148:477-487, 1992). Especially, approximately 5% of various solid cancers, such as lung cancer, breast cancer and colon cancer, are thought to develop into meningeal carcinomatosis when metastasizing to the brain. Cancer patients tend to develop this disease more frequently in recent years with increases in the survival time.
Among other metastatic brain tumors, meningeal carcinomatosis in particular results from meningeal irritation due to tumors, impeded circulation of CSF due to obstruction of the CSF pathway, infiltration of tumors into the cerebrospinal parenchyma, and infiltration of tumors into the cranial nerves or spinal nerves extending through the subarachnoid cavity, therefore presenting a wide variety of seriously aggravated lethal symptoms including headaches, encephalopathies, dyskinesia and sensory disturbances.
Meningeal carcinomatosis is treated generally by intrathecal administration of anticancer agents, topical application of radiation or the combination of both. For example, methotrexate (MTX) is usually intrathecally given singly or in combination with Cytosine Arabinoside (Ara-C) via an Ommaya reservoir placed in the lateral ventricle (Arch Neurol. 38:696-699, 1981, Cancer 49:219-222, 1982, Cancer 49:759-72, 1982, Neurology 33:1565-72, 1983, J. Clinical Ankle. 4.68-73, 1986, Clinical Oncol. 5:1655-62, 1987). The intrathecal administration of these anticancer agents achieves a therapeutic efficacy of about 40 to about 60% , clinically leads to temporary regression for a short period in some cases but fails to improve the usual performance status in other cases despite regression. Acute neurotoxicity and retarded necrotizing encephalopathy, side effects of MTX in prevalent use, impose limitations on the dose which is sufficient to clinically produce a satisfactory therapeutic effect, with the result that the effect achieved still remains to be improved (New England J. Med. 289:770-73, 1973).
FUDR for use in the present invention is an active metabolite of 5-fluorouracil (5-FU) and a known compound which has very high antitumor activity and which is used in the U.S. as a drug for treating the metastasis of colon cancer to the liver (Ann. Surg., 206:685-693, 1987, Ann. Intern. Med., 107:459-465, 1987, J. Clinical Oncol., 7:1646-1654, 1989, Arch. Surg., 125:1022, 1990, J. Clinical Oncol., 10:1112-1118, 1992, J. Clinical Oncol., 8:1885-1893, 1990, Lance, 344:1255-1260, 1994). Although the compound was clinically applied to glioblastoma and metastatic brain tumors by intravenous administration in a very few cases, the results achieved have yet to be established as standard therapeutic effects (Cancer 68:995-98, 1991).
Accordingly, in view of the current therapies for patients with metastatic brain tumors, especially with meningeal carcinomatosis, it is desired to develop a safe and effective method of treatment with QOL (quality of life) of the patient taken into consideration.